New product PBS listed August New product PBS listed July New product PBS listed June 2008

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1 August 08 ISSN Timely, independent information about new drugs Sitagliptin (Januvia) for type 2 diabetes mellitus New product PBS listed 02 Memantine (Ebixa) for dementia in moderately severe Alzheimer s disease 08 New product PBS listed July 2008 Duloxetine (Cymbalta) for major depressive disorder New product PBS listed June Escitalopram (Lexapro, Esipram) for generalised anxiety disorder and social anxiety disorder (social phobia) 18 New indications PBS listed Automatic egfr reporting its role in screening for kidney disease and drug-dosing decisions 24 NPS RADAR reviews the advantages and limitations In Brief Zolpidem and sleep-related behaviours Change to methotrexate pack sizes due to safety concerns Rivastigmine (Exelon) patch PBS listed for Alzheimer s disease Lercanidipine with enalapril (Zan-Extra) fixed-dose combination tablets PBS listed for hypertension Palliative care drugs added to the Emergency Drug (Doctor s Bag) Supplies 29 NPS is an independent, non-profit organisation for Quality Use of Medicines, funded by the Australian Government Department of Health and Ageing.

2 NPS RADAR provides timely, independent, evidence-based information on new drugs, research and PBS listings for general practitioners, specialists, pharmacists and other health professionals. 01 Can the new dogs perform the old tricks? Will today s new drug provide the same benefits as the old one we already have? This question frequently comes up when we are reviewing new medicines for NPS RADAR. Many new drugs are registered and funded on the basis of their effects on surrogate markers such as glycated haemoglobin (HbA 1c ) levels but without evidence that they affect the outcomes that matter to patients, such as the chances of myocardial infarction, losing vision or requiring dialysis. Trials looking at surrogate endpoints are quicker, simpler, smaller and cheaper than those looking directly at patient-relevant outcomes, and allow new drugs to come to market more quickly. But making clinical judgments based on surrogate data is never straightforward, and the true benefit harm profile is elusive. The usual caution advised when approaching new drugs applies more than ever. The glitazones and ezetimibe showed efficacy according to surrogate markers but more recently their effects on patient-relevant outcomes have been questioned as more evidence has emerged. The glitazones reduce HbA 1c levels, but they are useful for a narrowing group of patients because they increase the risk of heart failure and, in the case of rosiglitazone, possibly increase the risk of myocardial infarction. Adding ezetimibe to a statin further reduces low-density lipoprotein cholesterol levels, but a recent study using a different surrogate endpoint found no difference in carotid-artery intima-media thickness (a marker of progression of atherosclerosis) with the combination compared with simvastatin alone. 1 We await the results of ongoing studies of the effect of ezetimibe on the risk of cardiovascular events and death. In this issue of NPS RADAR we look at sitagliptin, a new medicine for type 2 diabetes. Sitagliptin has a different mechanism of action from those of other available blood-glucose-lowering drugs. Adding it to another oral blood-glucose-lowering drug can lower HbA 1c by an additional 0.5% to 1%. Nonetheless, it remains to be seen whether sitagliptin has the other benefits that come with the blood-glucose-lowering effects of metformin or indeed what sitagliptin s long-term safety profile will be. While sitagliptin is an option for people who cannot maintain glycaemic control on oral monotherapy and cannot take both metformin and a sulfonylurea, starting insulin has much to recommend it as an alternative, as insulin is known to reduce the risk of diabetes-related complications. Another new dog in this issue of NPS RADAR is estimated glomerular filtration rate (egfr) calculated using the Modified Diet in Renal Disease (MDRD) equation, which is now routinely reported by most laboratories. The MDRD egfr helps to signal early kidney disease but its role in determining drug dose adjustments is less straightforward. For people with significantly above- or below-average body size, the unadjusted MDRD egfr could lead to under- or overestimation of dose requirements. For critical-dose drugs and people sensitive to small differences in drug dosages, the Cockcroft Gault equation or a direct measurement of GFR should remain the basis for dose adjustments until MDRD egfr is validated for this purpose. References 1. Kastelein JJP, et al. N Engl J Med 2008;358: Timely, independent information about new drugs National Prescribing Service Limited National Prescribing Service Limited (NPS) is an independent, non-profit organisation for Quality Use of Medicines. We provide accurate, balanced, evidence-based information and services to help people choose if, when and how to use medicines to improve their health and wellbeing. We are member-based and work in partnership with health professionals, government, pharmaceutical industry and consumers. NPS is funded by the Australian Government Department of Health and Ageing.

3 Sitagliptin (Januvia) for type 2 diabetes mellitus (SI-ta-GLIP-tin) Summary Sitagliptin is the first of a new class of oral drugs, the dipeptidyl peptidase 4 (DPP-4) inhibitors, for improving glycaemic control in type 2 diabetes mellitus. The effect of sitagliptin on diabetes-related complications and mortality is not known. Sitagliptin is listed on the PBS for dual oral therapy with either metformin or a sulfonylurea, when a combination of these drugs is contraindicated or not tolerated. Insulin or a glitazone are other treatment options when metformin cannot be used with a sulfonylurea. 02 There is insufficient evidence to support the use of sitagliptin as monotherapy or triple oral therapy with metformin and a sulfonylurea. Sitagliptin is not associated with weight gain or an increased risk of hypoglycaemia. However, when choosing between treatment options consider that: insulin has been shown to reduce the risk of diabetes-related complications sitagliptin s efficacy and safety have not been compared with those of insulin weight gain and hypoglycaemia can still occur when sitagliptin is used with drugs that cause these effects (e.g. sulfonylureas) while there are safety concerns with the glitazones, the long-term benefit harm profile of sitagliptin is yet to be established. Adverse effects with sitagliptin include nasopharyngitis, upper respiratory tract infection, headache and nausea. Postmarketing reports of anaphylaxis, angioedema, rash, urticaria and exfoliative skin conditions (including Stevens Johnson syndrome) have occurred during treatment with sitagliptin. While a causal link is yet to be established, stop sitagliptin if a hypersensitivity reaction is suspected. Reduce the dose of sitagliptin in moderate to severe renal impairment. PBS listing Authority required Dual oral therapy with either metformin or a sulfonylurea in patients with type 2 diabetes whose HbA 1c is > 7% despite treatment with metformin or a sulfonylurea, and when a combination of metformin and a sulfonylurea is contraindicated or not tolerated. Sitagliptin is not listed on the Pharmaceutical Benefits Scheme for use in combination with metformin and a sulfonylurea (triple oral therapy), as monotherapy or in combination with a thiazolidinedione (glitazone). Reason for PBS listing The Pharmaceutical Benefits Advisory Committee recommended the listing of sitagliptin as dual oral therapy with metformin or a sulfonylurea on a costminimisation basis that is, similar efficacy and cost compared with rosiglitazone. 1 The equi-effective doses for this comparison were sitagliptin 100 mg daily and rosiglitazone 8 mg daily. 1

4 Sitagliptin (Januvia) 03 Place in therapy Sitagliptin is the first member of a new class of oral drugs for type 2 diabetes called dipeptidyl peptidase 4 (DPP-4) inhibitors. Sitagliptin is a treatment option for dual oral therapy with either metformin or a sulfonylurea, when the combination of metformin and a sulfonylurea is contraindicated or not tolerated. Insulin or a glitazone (rosiglitazone or pioglitazone) are alternatives to sitagliptin. The choice of drug should take into account the effect on diabetes-related clinical outcomes, the long-term safety profile and the patient s preference. There is insufficient evidence to support the use of sitagliptin as monotherapy or triple oral therapy with metformin and a sulfonylurea. Sitagliptin may be used with a glitazone for some patients 2 ; however, this combination has limited efficacy and safety data and is not PBS listed. The pharmacological action of sitagliptin differs from that of other antidiabetic drugs Incretin hormones (or incretins ), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine to control blood glucose levels after a meal. 2 Incretins are rapidly metabolised by the DPP-4 enzyme. 2 The activity and levels of incretins are reduced in people with type 2 diabetes. 3 Sitagliptin is an incretin enhancer that inhibits DPP-4 and thereby increases the levels of active incretins, prolonging their effect in stimulating insulin release and decreasing glucagon secretion. 2 This differs from the action of incretin mimetics such as the injectable drug exenatide which are GLP-1 receptor agonists. 3 DPP-4 inhibitors may also prolong the action of neuropeptides, including substance P, thereby increasing the risk of inflammatory and allergic reactions. 4 7 DPP-4 is found in T cells, raising theoretical concerns that this drug class may affect the immune system (see Safety issues). 5,6 The effect of sitagliptin on morbidity and mortality is unknown There are no data on the effects of sitagliptin on diabetes-related complications and mortality. Clinical trials have been short-term (12 52 weeks) and measured HbA 1c levels as a surrogate for clinical outcomes. 4 Sitagliptin has little to no effect on lipids or on reducing blood pressure, and its impact on cardiovascular events is not known. 2,8 15 In contrast there is evidence that metformin improves glycaemic control and reduces the incidence of diabetesrelated complications and mortality. 16 Sulfonylureas also improve glycaemic control and reduce the incidence of microvascular complications. 17 In light of their proven clinical benefits, metformin is combined with a sulfonylurea (glibenclamide, gliclazide, glimepiride or glipizide) when metformin alone does not adequately control blood glucose (HbA 1c > 7%). 18 Sitagliptin is an option for people who require combination therapy but are unable to use either metformin or a sulfonylurea Sitagliptin improves glycaemic control in combination with either metformin or a sulfonylurea (dual oral therapy) in patients who are inadequately controlled on metformin or sulfonylurea monotherapy. Consider sitagliptin when the combination of metformin and a sulfonylurea is contraindicated or not tolerated. The effect of sitagliptin 100 mg daily has been compared with that of placebo, a sulfonylurea or a glitazone in people with type 2 diabetes who are inadequately controlled on metformin or sulfonylurea monotherapy. 9 12,14 Patients in the trials had a mean baseline HbA 1c of %. 9 12,14 Adding sitagliptin to metformin for weeks reduced mean HbA 1c by % compared with adding placebo. 9,12,14 One trial that added sitagliptin to glimepiride found a mean reduction in HbA 1c of 0.6% compared with adding placebo. 10 More patients achieved a target HbA 1c < 7% when metformin was combined with sitagliptin (22 55%) than with placebo (3 38%). 9,12,14 Combining metformin with sitagliptin, glipizide or rosiglitazone provides similar improvements in glycaemic control. 11,14 The mean reduction in HbA 1c did not differ significantly between sitagliptin (0.51%) and glipizide (0.56%) in all patients treated in a 52-week trial. 11 Similar reductions in mean HbA 1c were found in another trial with sitagliptin 100 mg daily (0.73%) and rosiglitazone 8 mg daily (0.79%) after 18 weeks. 14 Refer to this review at for more information on intolerance and contraindications to metformin

5 Sitagliptin (Januvia) Greater reductions in HbA 1c occurred in patients with higher baseline levels. 8,10 12,14 However, there are limited data for sitagliptin in patients with severe hyperglycaemia (HbA 1c > 11%), as they were excluded from most trials.* The efficacy of sitagliptin in the later stages of diabetes is as yet unknown. Most patients in trials had diabetes for 3 5 years, and generally for no longer than 10 years. 4,12,14 Insulin or a glitazone are other options Starting insulin or dual oral therapy with a glitazone (rosiglitazone or pioglitazone) are alternatives to using sitagliptin when the combination of metformin and a sulfonylurea is contraindicated or not tolerated. Insulin has been shown to reduce the risk of diabetesrelated complications. 17 Oral treatments such as sitagliptin or a glitazone may be preferred by patients who cannot use metformin and a sulfonylurea but are reluctant to start insulin. However, the effect of these oral drugs on diabetes-related clinical outcomes is not known, and neither is their long-term safety profile. Insulin should not be delayed when oral drug therapy no longer controls blood glucose (for more information, see NPS News 56: Managing hyperglycaemia in type 2 diabetes). The efficacy and safety of sitagliptin have not been compared with those of insulin. Sitagliptin is not associated with changes in body weight or hypoglycaemia (see Safety issues). It may be a useful alternative to insulin or a glitazone for patients who are overweight. However, sitagliptin does not offset the weight gain or risk of hypoglycaemia caused by other drugs (e.g. sulfonylureas). Sitagliptin may be preferred to the glitazones for some patients in light of recent safety concerns over the use of these drugs, including an increased risk of cardiovascular events, peripheral fractures and diabetic macular oedema (see the NPS RADAR reviews Rosiglitazone (Avandia) and rosiglitazone with metformin (Avandamet) for type 2 diabetes mellitus and Pioglitazone (Actos) for type 2 diabetes mellitus ). However, when choosing between treatment options consider that the long-term benefit harm profile of sitagliptin is yet to be established (see Safety issues). There are limited data on using sitagliptin with drugs other than metformin or a sulfonylurea Do not use sitagliptin in combination with exenatide, insulin, acarbose or repaglinide. There are no data on the efficacy and safety of using sitagliptin with these drugs. 2,4 For patients who require the addition of insulin to improve glycaemic control, stop sitagliptin and maintain other oral drug therapy (for more information, see NPS News 56: Managing hyperglycaemia in type 2 diabetes). There is some evidence for using sitagliptin with a glitazone. In one 24-week trial, adding sitagliptin 100 mg daily to pioglitazone reduced mean HbA 1c by 0.7% compared with adding placebo. 13 The benefit of using this combination may be offset by the potential adverse effects associated with the glitazones (see Insulin or a glitazone are other options). Do not use sitagliptin as monotherapy or triple oral therapy Sitagliptin should not be used for type 2 diabetes inadequately controlled by diet and exercise alone. In the trials of initial drug therapy, sitagliptin reduced mean HbA 1c by 0.8% compared with placebo. 4 However, there is no evidence comparing its effect on glycaemic control or diabetes-related outcomes with that of metformin or sulfonylurea monotherapy. 4,15,19 There is limited evidence for using sitagliptin as triple oral therapy with metformin and a sulfonylurea, and this is not approved by the Therapeutic Goods Administration. Consider initiating insulin or triple oral therapy with a glitazone when the combination of metformin and a sulfonylurea does not improve glycaemic control. In a 24-week trial of patients who were inadequately controlled with metformin and glimepiride, adding sitagliptin 100 mg daily reduced mean HbA 1c by 0.9% compared with adding placebo. 10 However, the triple combination was associated with a greater risk of hypoglycaemia than dual oral therapy with sitagliptin and glimepiride * An open-label cohort from one study included patients with HbA 1c > 11%. 19

6 Sitagliptin (Januvia) 05 Safety issues Sitagliptin is associated with an increased risk of nasopharyngitis and upper respiratory tract infection, and it may cause headache and nausea. 2,5,6,9,13,14 These adverse effects were usually reported by fewer than 10% of patients in trials. 2,5,9,13,14 The overall incidence of clinical adverse events in trials (30 60% of patients) was similar between sitagliptin and placebo when combined with metformin or pioglitazone. 9,12 14 More patients experienced adverse events with sitagliptin (56%) than with placebo (41%) when used in combination with glimepiride. 10 This was mainly because of an increased risk of hypoglycaemia. 10 The long-term benefit harm profile of sitagliptin is not established. Postmarketing reports of serious hypersensitivity reactions have occurred. 2 Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online ( or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website ( Be vigilant for potential adverse effects Long-term safety data for sitagliptin are currently not available. In clinical trials sitagliptin did not increase the risk of serious adverse effects compared with placebo 4 ; however, most patients were only followed for less than a year. Sitagliptin may cause adverse effects in various tissues including the skin, gastrointestinal tract, skeletal muscle and nervous system. 5,6 Those reported more frequently by patients in trials taking sitagliptin (compared with placebo) included abdominal pain, cough, arthralgia, myalgia, osteoarthritis, pain in the extremities or back, fatigue and dizziness. 5,6,8,9,11,13 Be vigilant for hypersensitivity reactions and infections during treatment with sitagliptin. Inhibition of DPP-4 in T cells is a potential safety concern, although the clinical and pre-clinical data for sitagliptin do not suggest a major effect on T cell immune responses. 5,6 The safety of using sitagliptin in people with underlying immune or allergic conditions is not known. A meta-analysis of randomised controlled trials found a slightly higher incidence of all-cause infections among patients treated with sitagliptin, compared with placebo (relative risk 1.29, 95% confidence interval 1.09 to 1.52). 4 The type of infections mostly reported were nasopharyngitis, pharyngitis, upper respiratory tract infection and urinary tract infection. 2,4 6,8,9,11,13,14,20 Infections characteristic of impaired T cell function, such as herpes simplex virus, were not reported more frequently with sitagliptin, compared with placebo. 6 There have been postmarketing reports of anaphylaxis, angioedema, rash, urticaria and exfoliative skin conditions, including Stevens Johnson syndrome, with sitagliptin. 2 These reactions occurred within 3 months of starting treatment, with some reports after the first dose. 2 One patient receiving sitagliptin withdrew from a trial because of urticaria and angioedema. 13 While a causal link has not been established, sitagliptin must be stopped if a hypersensitivity reaction is suspected, and other drug therapy initiated. 2 Sitagliptin was associated with very small increases in serum creatinine concentrations in placebo-controlled trials. 6 The changes were not clinically significant, but their magnitude was greater in patients with moderate to severe renal impairment. 6 The long-term effects of sitagliptin on the kidney are unknown. Be aware that rapidly deteriorating renal function increases the risk of lactic acidosis with use of metformin, and renal impairment increases the risk of hypoglycaemia with use of sulfonylureas 18 either of which may be used with sitagliptin. Sitagliptin has a neutral effect on weight Sitagliptin does not appear to alter body weight. Combining sitagliptin with metformin, a sulfonylurea or a glitazone is unlikely to cause additional weight loss or weight gain. However, it is not known if sitagliptin treatment remains weight-neutral in the long term. The mean change in body weight in trials of sitagliptin with metformin ( 0.4 to 0.7 kg) was similar to that of placebo with metformin. 9,12,14 Sitagliptin did not affect weight loss with metformin, whereas glipizide or rosiglitazone led to weight gain with metformin. 11,14

7 Sitagliptin (Januvia) Sitagliptin does not attenuate the weight gain associated with a sulfonylurea or glitazone. Patients who took sitagliptin or placebo with pioglitazone gained a mean weight of 1.8 kg and 1.5 kg, respectively. 13 Sitagliptin combined with glimepiride increased mean weight in one trial by 1.2 kg, compared with placebo and glimepiride. 10 Low hypoglycaemic risk unless combined with a sulfonylurea Sitagliptin lowers blood glucose levels only if they are elevated, so it is not expected to cause hypoglycaemia. 2 Sitagliptin did not increase the rate of hypoglycaemia compared with placebo when used as monotherapy or in combination with metformin or pioglitazone. 8,9,12 15,19 Severe episodes of hypoglycaemia were not reported with sitagliptin in trials. 4 Adding sitagliptin to metformin poses a lower risk of hypoglycaemia than adding a sulfonylurea. 5,11 The proportion of patients in a trial who reported at least 1 episode of hypoglycaemia was 4.9% with sitagliptin and 32% with glipizide, when combined with metformin over 52 weeks. 11 By contrast, combining sitagliptin with a sulfonylurea appears to increase the risk of hypoglycaemia compared with a sulfonylurea alone (see Dosing issues). More patients reported hypoglycaemia in one trial with sitagliptin (12%) than with placebo (2%) when added to glimepiride, either alone or with metformin. 10 The risk of hypoglycaemia with sitagliptin in combination with insulin or exenatide has not been studied. There are also no data on the use of sitagliptin with sulfonylureas other than glimepiride. Hypoglycaemia is a greater risk with glibenclamide or glimepiride, compared with glipizide or gliclazide, especially in the elderly and those with renal or hepatic impairment. 18 Dosing issues The recommended dose of sitagliptin is 100 mg once daily, taken with or without food. 2 When combining sitagliptin with a sulfonylurea, the dose of the sulfonylurea may need to be decreased to reduce the risk of hypoglycaemia. 2 Reduce dose in moderate to severe renal impairment Sitagliptin is primarily cleared by the kidney, and dosage reduction is required in patients with moderate to severe renal impairment. 2 For patients with creatinine clearance of 30 to < 50 ml/min, the recommended dose of sitagliptin is 50 mg once daily. 2 For patients with creatinine clearance < 30 ml/min or end-stage renal failure requiring haemodialysis or peritoneal dialysis, the recommended dose is 25 mg once daily. 2 Information for patients Inform patients that sitagliptin is a new drug for type 2 diabetes that improves glycaemic control when added to existing therapy. However, the long-term benefits and adverse effects of sitagliptin are unknown. Weight gain and hypoglycaemia are not associated with sitagliptin in combination with metformin. However, advise patients using sitagliptin with a sulfonylurea that these adverse effects may still occur. Alert patients to the potential for adverse effects with sitagliptin, particularly: infections of the nasopharyngeal and upper respiratory tract skin reactions swelling of the face, lips, mouth, tongue or throat. Reinforce to patients that lifestyle changes including a healthy diet and exercise remain important for controlling blood glucose in conjunction with drug therapy. Discuss the Januvia consumer medicine information (CMI) leaflet with the patient. Medicine Update An NPS Medicine Update leaflet on sitagliptin is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with those of other medicines. 06

8 Sitagliptin (Januvia) References Australian Government Department of Health and Ageing. March 2008 PBAC Outcomes Positive Recommendations. /main/publishing.nsf/content /72BFC3A986C01665CA25742D0010F20B/$File /03-08%20Positive%20decisions%20website %20ver%202.pdf (accessed 5 May 2008). 2. Merck Sharp & Dohme (Aust.) Pty Ltd. Januvia Product Information. 21 December Deacon CF. Diabetes Obes Metab 2007;9(Suppl.1): Richter B, et al. Cochrane Database Syst Rev 2008; Art. No: CD DOI: / CD pub2. 5. European Medicines Agency (EMEA). European Public Assessment Report (Januvia): Scientific Discussion /januvia/h-722-en6.pdf (accessed 5 May 2008). 6. Food and Drug Administration (FDA). Center for Drug Evaluation and Research: Medical Review of Januvia (sitagliptin phosphate) 2006; Application Number: : /2006/021995s000_MedR.pdf (accessed 28 May 2008). 7. Grouzmann E, et al. JAMA 2007;298: Aschner P, et al. Diabetes Care 2006;29: Charbonnel B, et al. Diabetes Care 2006;29: Hermansen K, et al. Diabetes Obes Metab 2007;9: Nauck MA, et al. Diabetes Obes Metab 2007;9: Raz I, et al. Current Med Res Opin 2008;24: Rosenstock J, et al. Clin Ther 2006;28: Scott R, et al. Diabetes Obes Metab 2008; DOI: /j x. 15. Scott R, et al. Int J Clin Pract 2007;61: UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: Australian Medicines Handbook, Goldstein BJ, et al. Diabetes Care 2007;30: Amori RE, et al. JAMA 2007;298: Date prepared: June 2008 The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.

9 Memantine (Ebixa) for moderately severe Alzheimer s disease (me-man-teen) Summary Memantine is PBS listed for use in moderately severe Alzheimer s disease. In contrast, the cholinesterase inhibitors are PBS listed for patients with mild to moderate Alzheimer s disease. Memantine does not stop the progression of Alzheimer s disease. Short-term trials have found modest improvements in scores on rating scales of cognitive, psychological and behavioural functioning. The clinical importance of these outcomes is yet to be established. There is no reliable evidence of memantine s long-term effectiveness. 08 As with the cholinesterase inhibitors, not all patients respond to treatment. Review patients regularly and discontinue after 6 months if there is no improvement. There have been no head-to-head trials of memantine against any of the cholinesterase inhibitors. There is a lack of evidence on the efficacy of memantine among people who cannot tolerate or do not respond to a cholinesterase inhibitor. If switching, consider gradually reducing the dose of the cholinesterase inhibitor while gradually increasing the dose of memantine. Memantine is contraindicated in patients with renal impairment (creatinine clearance 50 ml/min) or a history of seizures. PBS listing Authority required Initial and continuing treatment of moderately severe Alzheimer s disease as monotherapy. This is narrower than the TGA-approved indication for memantine to treat moderately severe to severe Alzheimer s disease. The diagnosis of moderately severe Alzheimer s disease must be confirmed by a specialist, and the patient s baseline Mini-Mental State Examination (MMSE)* score must be 10 14, inclusive. Memantine can be prescribed to patients with an MMSE score of 9 if the patient: is from a different cultural background has an intellectual or sensory disability has inadequate English, prominent dysphasia or very limited education. In these situations the MMSE assessment must be supplemented with results of the Clinician s Interview Based Impression of Severity (CIBIS). Continuing treatment requires a demonstrated improvement in cognitive function within 6 months of initiating therapy, as measured by a 2-point increase in the baseline MMSE score, or, in those for whom the CIBIS was used to assess disease severity, by a rating of very much improved or much improved on the Clinician s Interview Based Impression of Change (CIBIC) scale. The PBS only allows treatment with one PBS-subsidised drug (memantine or a cholinesterase inhibitor) at a time. * A 30-point cognition scale in which lower scores indicate poorer function. The Standardised Mini-Mental State Examination (SMMSE) may also be used to assess baseline cognition. A 7-point subjective overview of a patient s improvement in general and across the domains of cognition, functional ability and behaviour.

10 Memantine (Ebixa) 09 Reason for PBS listing Several previous applications for memantine to be PBS listed for Alzheimer s disease were rejected by the Pharmaceutical Benefits Advisory Committee (PBAC). 1 While the successful submission argued that memantine was no worse than the cholinesterase inhibitors (donepezil, rivastigmine and galantamine), the PBAC disagreed. 2 Instead, memantine was recommended for listing on 1 July 2008 after the PBAC decided that, while the drug was less effective than the cholinesterase inhibitors (although this was associated with some uncertainty), it was also less costly and was associated with fewer adverse effects. Place in therapy Memantine is an N-methyl-D-aspartate (NMDA) antagonist that is thought to protect against elevated levels of glutamate. Memantine is PBS listed for the treatment of moderately severe Alzheimer s disease (MMSE 10 14). In contrast, the cholinesterase inhibitors which are an unrelated pharmacological class are PBS listed for the treatment of mild to moderate Alzheimer s disease (MMSE 10 24). Like the cholinesterase inhibitors, memantine does not stop the progression of Alzheimer s disease. Clinical trials of memantine have shown benefits over a 6-month period. Not all patients respond to treatment with drugs for the symptomatic treatment of dementia. Guidelines suggest that patients who do not stabilise or improve in the first few months of therapy are unlikely to have any subsequent benefit. 3 Patients should be reviewed regularly and the drug discontinued if they do not improve i.e. if they do not achieve a MMSE score 2 points above their baseline score. Short-term effectiveness is modest No studies have been performed solely among people with moderately severe Alzheimer s disease (MMSE score 10 14). However, some information on the efficacy of memantine can be inferred from trials among people with moderate to severe Alzheimer s disease (MMSE 3 14) and trials among people with mild to moderate Alzheimer s disease (MMSE 10 23). A Cochrane review 4 of 6-month trials of memantine in people with moderate to severe Alzheimer s disease reported marginally less deterioration among people taking memantine compared with those taking placebo. These included: a difference of 3.0 points on a 100-point measure of cognitive function a difference of 1.3 points on a 54-point scale of functional ability a difference of 2.8 points on a 144-point measure of behaviour and mood a 0.3 point difference on a 7-point subjective clinical impression of change scale. While these differences are statistically significant, they are small and may not represent a clinically meaningful change. Long-term trials of memantine are required to assess whether these differences translate into improvements in patient outcomes (e.g. delaying institutionalisation). Memantine did not show the same effects among people with less severe Alzheimer s disease. Analyses performed in the Cochrane review of 6-month trials of memantine in patients with mild to moderate Alzheimer s disease found that memantine had no benefit on behaviour or functional ability compared with placebo and made only a 1-point difference on a 70-point cognitive assessment tool (the ADAS-cog). 4 A 4-point difference is commonly accepted as being clinically detectable on this scale. 3 Only some patients will respond to drug therapy Review patients regularly and continue drug therapy only if cognition improves within 6 months of initiating therapy ( 2 points increase from baseline MMSE score). While an improvement on an assessment scale may be statistically significant, this may not translate into a clinically meaningful benefit. In trials in which patients were classified according to whether they showed a predefined clinically meaningful response only some responded to memantine therapy. Bakchine et al defined responders as patients showing marked improvement in cognitive function (change in ADAS-cog score 4) and global stabilisation or improvement (CIBIC+ score 4). At 6 months there was no significant difference in the proportion of patients receiving placebo (25%) and those receiving memantine (31%) who met this definition. 5

11 Memantine (Ebixa) Reisberg et al defined responders as patients with stabilisation or improvement on CIBIC+ and an improvement or no change in cognition or disability. At 28 weeks, 29% of patients on memantine and 10% of patients on placebo were classified as responders (p < 0.001). 6 The benefit of long-term treatment is unproven No randomised trial of memantine in Alzheimer s disease has studied efficacy for more than 7 months. Efficacy data exist for a subgroup of patients who chose to stay on extended open-label memantine after participating in a randomised clinical trial. This may introduce bias because people who continued open-label memantine were most likely those who responded to treatment and tolerated the drug. During a 6-month extension study the condition of patients who had received memantine in the initial randomised trial continued to deteriorate. Functional ability deteriorated significantly faster during the second 6-month period while cognition continued to decline at a steady rate. 7 There are no head-to-head trials of memantine and the cholinesterase inhibitors There are no head-to-head comparisons of memantine with any of the cholinesterase inhibitors. An indirect comparison was made in the PBAC submission, comparing randomised trials of memantine against randomised trials of the cholinesterase inhibitors, using placebo as the common comparator. Ideally a head-to-head randomised trial comparing memantine with the cholinesterase inhibitors would help define relative efficacy. There is limited evidence to support combination therapy with memantine and a cholinesterase inhibitor There is limited evidence to support combination therapy. A 6-month randomised trial (n = 404) in patients with moderate to severe Alzheimer s disease reported that those taking memantine and donepezil performed marginally better on measures of cognition, function and behaviour than people taking donepezil and placebo. 9 In contrast, a 6-month randomised trial (n = 433) of addition of memantine or placebo to a stable dose of a cholinesterase inhibitor (donepezil, rivastigmine or galantamine) in patients with mild to moderate Alzheimer s disease found no difference between the groups. 10 The PBS listing only allows subsidisation of either memantine or a cholinesterase inhibitor. A lack of evidence on the efficacy of switching from a cholinesterase inhibitor to memantine There is a lack of evidence on the efficacy of memantine among people who are unable to tolerate or do not respond to a cholinesterase inhibitor. Hypothetically, memantine could benefit these patients, as it has a different mechanism of action to that of the cholinesterase inhibitors. A single 8-week switching study among patients who no longer benefited from donepezil has been published. 11 Participants began memantine after either stopping donepezil abruptly (n = 24) or gradually tapering their donepezil dose over 2 weeks (n = 22). During the first week, 4 patients in the abrupt discontinuation group experienced an adverse event (arthrosis, pruritus or vertigo) while none were reported in the tapered group. The study was not designed to assess efficacy. Memantine is only PBS approved for patients with an MMSE score of If switching a patient who meets this criterion, consider gradually reducing the cholinesterase inhibitor dose. The memantine dose may be gradually increased while tapering the dose of cholinesterase inhibitor or after it has been stopped. Fewer people taking memantine developed agitation compared with placebo During clinical trials against placebo, agitation was significantly less commonly reported among patients with moderate to severe Alzheimer s disease who took memantine, compared with those using placebo. The effect is small, as 17 patients needed to be treated for 6 months to prevent 1 case of agitation A second open-label extension trial only investigated safety and tolerability and did not report any efficacy data. 8

12 Memantine (Ebixa) 11 Safety issues Memantine is contraindicated in patients with renal impairment (creatinine clearance 50 ml/min) or a history of seizures. 12,13 In clinical trials up to 25% of participants stopped taking memantine; in 6% to 12% of participants this was because of adverse effects. 5,6,9,10,14,15 However, adverse effects are more difficult to assess in patients with later-stage dementia 16 so these rates may be an underestimate. Common adverse effects include confusion, dizziness, drowsiness, headache, insomnia, agitation and hallucinations. 12 In one clinical trial hypertension was more common in the memantine group than in the placebo group (7.9% vs 2.3%, p = 0.01). 15 There have been single case reports of hepatitis with cholestasis 17, psychosis 18, spontaneous bruising 19 and exacerbation of myoclonic jerks. 20 Avoid using other N-methyl-D-aspartate antagonists (amantadine, ketamine, or dextromethorphan) with memantine, as this may increase both the incidence and severity of adverse effects. 13 Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online ( or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website ( Dosing issues Memantine is available as a 10 mg tablet or 10 mg/ml oral solution with a calibrated dropper. The recommended maintenance dose is 20 mg/day (10 mg twice a day). Start memantine as shown in Table 1. Take memantine (tablets and drops) with liquid. Memantine can be taken with or without food. Table 1: Initial dose titration Week Week 1 Week 2 Week 3 Week 4 Dose Morning: half a tablet or 10 drops of solution Morning: half a tablet or 10 drops of solution Evening: half a tablet or 10 drops of solution Morning: 1 tablet or 20 drops of solution Evening: half a tablet or 10 drops of solution Morning: 1 tablet or 20 drops of solution Evening: 1 tablet or 20 drops of solution Information for patients and carers Discuss the following with the patient and/or carers: memantine does not work for everyone and the response to the drug cannot be predicted common adverse effects include confusion, dizziness, drowsiness, headache, insomnia, agitation and hallucinations drug therapy will be trialled for 6 months continuing the drug after 6 months requires demonstrated improvement in cognitive function as measured by an increase of at least 2 points from baseline on the MMSE. Discuss the Ebixa consumer medicine information (CMI) leaflet. Alzheimer s Australia (toll free ) offers information and support for people with Alzheimer s disease and their carers and families. The Commonwealth National Respite for Carers Program provides information and help to arrange access to respite care for carers of people with chronic conditions (phone ).

13 Memantine (Ebixa) References 1. Pharmaceutical Benefits Branch. Memantine hydrochloride, tablet, 10 mg and oral solution, 10 mg per ml, Ebixa, March Canberra: Australian Government Department of Health and Ageing, /Content/pbac-psd-memantine-hydrochloride-mar07 (accessed 22 May 2008). 2. Pharmaceutical Benefits Advisory Committee. Positive Recommendations made by the PBAC March Canberra: Australian Government Department of Health and Ageing, /main/publishing.nsf/content/pbacrec-mar08-positive (accessed 5 May 2008). 3. Qaseem A, et al. Ann Inter Med 2008;148: McShane R, et al. Cochrane Database Syst Rev (Online) 2006:CD Bakchine S, Loft H. J Alzheimers Dis 2007;11: Reisberg B, et al. N Engl J Med 2003;348: Reisberg B, et al. Arch Neurol 2006;63: Ott BR, et al. J Neurol 2007;254: Tariot PN, et al. JAMA 2004;291: Porsteinsson AP, et al. Curr Alzheimer Res 2008;5: Waldemar G, et al. Int J Geriatr Psychiatry Australian Medicines Handbook Lundbeck Australia Pty Ltd. Ebixa product information 26 June Peskind ER, et al. Am J Geriatr Psychiatry 2006;14: van Dyck CH, et al. Alzheimer Dis Assoc Disord 2007;21: Committee for Medicinal Products for Human Use. Guideline on medicinal products for the treatment of Alzheimer's diease and other dementias (draft), Report No.: Doc. Ref. CPMP/EWP/553/95 Rev Ferrara N, et al. Ann Intern Med 2008;148: Huey ED, et al. J Clin Psychiatry 2005;66: Scharf SL, et al. Intern Med J 2005;35: Papageorgiou SG, et al. J Clin Psychopharmacol 2007;27: Date prepared: June 2008 The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient. 12

14 Duloxetine (Cymbalta) for major depressive disorder (due-loks-e-teen) Summary Duloxetine is a serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant, in the same class as venlafaxine. Duloxetine has similar efficacy to that of other antidepressants, including SSRIs and venlafaxine. Duloxetine should not be used in children and adolescents aged < 18 years. There is no evidence for its use in this population and antidepressants increase the risk of suicidal thinking and behaviour in children, adolescents and young adults. Nausea is common when starting duloxetine and can cause patients to stop treatment. Venlafaxine or escitalopram may be better tolerated at the recommended starting doses. Duloxetine is contraindicated in combination with strong inhibitors of CYP1A2 (e.g. ciprofloxacin). 13 Monitor the blood pressure of people with cardiovascular disease, as it can be increased by duloxetine. To avoid discontinuation symptoms such as dizziness, nausea, headache and paraesthesia, halve the dose for 2 or more weeks before stopping. PBS listing Restricted benefit Duloxetine (Cymbalta) 30 mg and 60 mg capsules can be prescribed on the Pharmaceutical Benefit Scheme (PBS) for people with a major depressive disorder. 1 The 30 mg capsule is listed as a month s supply with no repeats. People with renal impairment who require this strength on an ongoing basis will need an authority for any repeats. Reason for PBS listing The Pharmaceutical Benefit Advisory Committee (PBAC) considered duloxetine to be as effective as venlafaxine (Efexor-XR), but with more adverse effects in the first 6 weeks of therapy. In the following 6 weeks the incidence of adverse effects was similar for the two drugs. 2 The PBAC had previously accepted as plausible the argument that the discontinuation rate with duloxetine could be reduced by slower dose titration. However, it remained concerned that in trials twice as many people stopped taking duloxetine because of adverse events as stopped taking venlafaxine. 3 Place in therapy Antidepressants are effective in moderate or severe major depressive disorder. There are many different antidepressants available in a number of classes, with similar efficacy but differences in adverse effects. Duloxetine provides another treatment option, but does not offer any particular advantages over existing therapies.

15 Duloxetine (Cymbalta) Duloxetine is a serotonin and noradrenaline reuptake inhibitor Like venlafaxine, duloxetine has a primary effect of potentiating serotonergic and noradrenergic activity in the CNS. The adverse-effect profile of duloxetine, as with venlafaxine, includes serotonergic effects similar to those of SSRIs, and noradrenergic effects. The latter include mydriasis a hazard for people with raised intraocular pressure or at risk of acute narrow-angle glaucoma and a slight increase in heart rate and blood pressure. People with cardiovascular disease may need additional blood pressure monitoring. 4 There have been 2 published case reports of tachycardia and worsening symptoms in people with advanced heart failure. 5 Psychological therapies are recommended before antidepressants in mild depression Drug therapy is not indicated initially in adjustment disorder or milder forms of depression. 6 9 Major depression can be diagnosed according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), with severity depending on the number of depressive symptoms, the degree that functioning is impaired, the history of depression and the risk of suicide. 6,7,9 Specific psychological therapies such as cognitive behavioural therapy (CBT) and interpersonal therapy (IPT) are recommended: as first-line treatment for mild or moderate major depression as adjunctive therapy in moderate to severe major depression (if an adequate response is not achieved with a drug alone) to prevent relapse in people who are in remission. 7 Duloxetine has similar efficacy to that of other antidepressants Newer antidepressants, including duloxetine, selective serotonin reuptake inhibitors (SSRIs), moclobemide, mirtazapine, reboxetine and venlafaxine, do not differ greatly in efficacy or tolerability. 10,11 While there is evidence that the newer non-ssris may have a modest efficacy advantage over SSRIs, the difference is unlikely to be clinically significant (24 patients would need to be treated with the alternative drug to achieve 1 additional response). 12 A combined analysis of 2 double-blind randomised controlled trials comparing duloxetine 60 mg daily with venlafaxine 150 mg daily found that the 2 drugs had similar efficacy after 6 weeks of treatment. 2,13 Furthermore, 2 trials comparing duloxetine 60 mg daily and escitalopram (Esipram, Lexapro) mg daily, found that these drugs had similar efficacy after 8 weeks of treatment. 14,15 In all 4 trials more people dropped out in the duloxetine groups than in the comparator groups (see Safety issues). Safety issues Duloxetine causes a similar range of adverse effects to those seen with venlafaxine or the SSRIs. Nausea is the most common adverse effect and may cause some people to stop treatment. Antidepressants are associated with increased suicidality in children, adolescents and young adults, and duloxetine is unlikely to be an exception. Duloxetine may exacerbate existing liver disease, including alcohol-related liver damage. As with SSRIs, prescribers should guard against serotonin toxicity (also known as serotonin syndrome) caused by co-prescribing with other serotonergic drugs. Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online ( or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website ( Ask about suicidal thoughts and assess risk Assessing depressive symptoms should include asking if the patient has had suicidal thoughts. 6 The initial period of antidepressant treatment is recognised as a risk period for suicide attempts. 6 For further information about risk assessment refer to NPS Prescribing Practice Review 27: Managing Depression. Duloxetine should not be used in children and adolescents aged < 18 years Duloxetine is not registered for use by people aged < 18 years, and there are no clinical trials in this age group. 4 Antidepressants have an uncertain balance of benefits and harms for children and adolescents with major depressive disorder: see the Adverse Drug Reactions Advisory Committee (ADRAC) advice about use of SSRI antidepressants in children and adolescents and the NPS RADAR review Selective serotonin reuptake inhibitors in child and adolescent depression. 14

16 Duloxetine (Cymbalta) 15 A comprehensive analysis of clinical trials by the US Food and Drug Administration found that antidepressants increased the risk of suicidal thinking and behaviour in children, adolescents and young adults (up to age 24). There were no completed suicides among those < 18 years, and too few among adults to draw a conclusion. 16 Nausea is common when starting duloxetine In placebo-controlled trials, 20% of participants receiving duloxetine experienced nausea 4 and about 1% discontinued because of it. 17 The nausea began within a few days of starting the drug and persisted for a week on average, and was mostly mild or moderate in intensity. 17 Other common or very common adverse effects of duloxetine include headache, dry mouth, constipation, diarrhoea, decreased appetite, increased sweating, dizziness, fatigue, somnolence and insomnia. 4 Venlafaxine or escitalopram may be better tolerated than duloxetine at the recommended starting doses In clinical trials, duloxetine 60 mg daily caused more discontinuations due to adverse effects than either venlafaxine 150 mg daily or escitalopram mg daily In a pooled analysis, 12% of participants assigned to duloxetine 60 mg daily had discontinued because of adverse effects, compared with 6% of participants assigned to venlafaxine 150 mg daily, after 6 weeks of treatment. 13 Duloxetine 60 mg daily caused more insomnia and constipation than escitalopram mg daily after 8 weeks of treatment. 14,15 It also caused more nausea and dizziness than venlafaxine 150 mg daily after 6 weeks of treatment. 13 Starting with a lower dose of duloxetine (30 mg daily) or taking duloxetine with food may reduce nausea (see Dosing issues). Duloxetine is contraindicated for people with hepatic impairment and should not be taken by heavy drinkers Plasma clearance of duloxetine is slowed considerably in people with hepatic impairment. In addition, duloxetine may aggravate pre-existing liver disease. 4 Postmarketing reports have described isolated cases of liver failure, including fatalities, which were possibly related to duloxetine. 4,18 Most cases were in people with past or current risk factors for liver injury, including alcohol abuse. 4 In trials for any indication, alanine aminotransferase (ALT) elevations to > 3 times the upper limit of normal occurred in 1% of people who took duloxetine, compared with 0.2% of placebo-treated individuals. Evaluate the patient s level of alcohol consumption when considering duloxetine and avoid prescribing it for heavy drinkers. Duloxetine should not be used together with strong inhibitors of CYP1A2 Strong inhibitors of CYP1A2 (such as ciprofloxacin) may increase the plasma concentration of duloxetine by preventing its metabolism. 4 Duloxetine is itself a moderate inhibitor of CYP2D6 and therefore may interact with drugs that are extensively metabolised by CYP2D6. 4 This may lead to clinically significant increases in plasma levels of CYP2D6 substrates that have a narrow therapeutic index (such as metoprolol, perhexiline, phenothiazines, or flecainide). 4,19,20 Similarly, duloxetine has the potential to reduce the analgesic effect of codeine by preventing its activation by CYP2D6. 21 Avoid co-prescribing duloxetine with other drugs that can increase serotonin levels Duloxetine may interact with other serotonergic drugs to cause serotonin toxicity (also known as serotonin syndrome). These drugs include SSRIs, venlafaxine, tricyclic antidepressants, monoamine oxidase inhibitor (MAOI) antidepressants (including moclobemide), triptans, tramadol, pethidine, fentanyl, St John s wort and the illicit drugs MDMA ( ecstasy ), cocaine and LSD. 4,22,23 Serotonin toxicity can range from mild to life threatening. 23 The risk of toxicity and drug interactions from antidepressant combinations outweighs the marginal evidence of added efficacy in almost all cases. 24 Dosing issues The usual dose is a single 60 mg capsule once daily. A reduced dose of 30 mg once daily is indicated for people with end-stage renal disease and may also be used for titration for the first week of therapy. Stopping duloxetine abruptly can cause symptoms such as dizziness and nausea, so tapering is advised.

17 Duloxetine (Cymbalta) The standard dose is 60 mg once daily, with or without food Doses below 60 mg daily were not consistently superior to placebo in clinical trials. On the other hand, there was no adequate evidence that doses above 60 mg provided any benefit to people who did not respond to 60 mg daily. 4 Duloxetine is formulated with an enteric coating designed to protect the drug from the acid environment of the stomach. Under strongly acidic conditions, duloxetine breaks down into pharmacologically inactive compounds, including naphthol, an irritant to the gastric and intestinal mucosa. A lower starting dose or taking duloxetine with food may reduce nausea Some patients may benefit from a lower starting dose of 30 mg once daily for 1 week before increasing to 60 mg once daily, if adverse effects are a concern. 4 There is some evidence that this alternative initiation regimen results in less nausea. 25,26 Alternatively, taking duloxetine with food (at either dose) improves tolerability, according to limited evidence from one study. 26 While the lower starting dose may reduce adverse effects, it is unlikely to eliminate them. It may also delay the onset of therapeutic effect. 25,26 One trial (for generalised anxiety disorder rather than depression) that used the lower initial starting dose still found significantly more nausea with duloxetine than with placebo (32% vs 14%) and a significant rate of discontinuation due to adverse events (14% vs 2%). 27 Reduce the dose for people with end-stage renal disease People with a creatinine clearance 30 ml/min do not require any dose adjustment. For people with more severe renal impairment than this (e.g. in end-stage renal disease), use a lower dose of 30 mg once daily. 4 Duloxetine is toxic in overdose There have been fatal acute overdoses with duloxetine alone at doses of 1000 mg and above. However, most fatal overdoses have involved combinations with other drugs. 4 Signs and symptoms of overdose (either with duloxetine alone or with mixed drugs) included somnolence, coma, serotonin toxicity, seizures, syncope, tachycardia, hypotension, hypertension and vomiting. 28 Prescribe and dispense duloxetine in the smallest quantity practicable, to reduce the risk of overdose. 4 Switch to or from another antidepressant as for venlafaxine Like venlafaxine, duloxetine has a short washout period, but should be withdrawn slowly to prevent discontinuation symptoms (see Halve the dose for 2 or more weeks before stopping). There is potential for a dangerous interaction with MAOIs: do not administer duloxetine within 14 days of stopping an MAOI, and wait at least 5 days after stopping duloxetine before starting an MAOI. 4 The risk of serotonin toxicity is lower for moclobemide, but concomitant use is not recommended. 29 Halve the dose for 2 or more weeks before stopping As with other SSRI and SNRI antidepressants, stopping duloxetine abruptly can cause adverse effects. About 40% of trial participants experienced adverse events in the 1 2 weeks after abrupt discontinuation. 30 About 40% of these events were mild, and 10% were severe. Symptoms associated with discontinuation included dizziness, nausea, headache, paraesthesia, vomiting, irritability and nightmares. The duloxetine product information recommends tapering the dose when discontinuing, by switching to the 30 mg strength or by taking duloxetine on alternate days, for a period of not less than two weeks. 4 Discontinuation symptoms were less common with duloxetine than with escitalopram or venlafaxine in two trials. In one trial, about 20% of venlafaxine users reported the most common symptom of dizziness, compared with 15% of duloxetine users. 13 In the other trial, which used a longer taper period of 2 weeks, 11% of escitalopram users reported dizziness, compared with 6% of duloxetine users. 15 Information for patients People with depression require careful counselling to encourage persistence with medication. Explain that mood may not improve immediately, and that initial side effects usually decrease with time. Encourage patients and carers to seek urgent medical assistance in the event of suicidal thoughts or behaviours (particularly when these are new or worsening). 16

18 Duloxetine (Cymbalta) Advise patients: not to chew, crush or open the capsules because this will stop the medication from working and may irritate the digestive system that side effects such as nausea, dizziness and headache are quite common but tend to decrease after a week or so; taking the capsule with a meal may reduce nausea not to stop taking duloxetine abruptly, because of possible withdrawal effects such as dizziness or nausea to consult a doctor or pharmacist before using any herbal medicines or nutritional supplements, as these may interact with duloxetine to cause side effects to consult a doctor or pharmacist before using any migraine medicines or strong painkillers such as codeine or tramadol, as these may interact with duloxetine to drink alcohol only lightly or not at all, to avoid harmful effects on the liver. Discuss the Cymbalta consumer medicine information (CMI) leaflet with the patient. Medicine Update An NPS Medicine Update leaflet on duloxetine is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with those of other medicines. 17 References 1. Australian Government Department of Health and Ageing. March 2008 PBAC outcomes: positive recommendations. /internet/main/publishing.nsf/content/pbacrec-mar08 -positive (accessed 1 May 2008). 2. Australian Government Department of Health and Ageing. Public summary document for duloxetine hydrochloride, capsules, 30 mg and 60 mg, Cymbalta March /wcms/publishing.nsf/content/pbac-psd-duloxetine -mar08 (accessed 19 June 2008). 3. Australian Government Department of Health and Ageing. Public summary document for duloxetine hydrochloride, capsules, 30 mg and 60 mg, Cymbalta July /main/publishing.nsf/content/pbac-psd-duloxetine -july07 (accessed 23 April 2008). 4. Eli Lilly Australia. Cymbalta product information. 21 January Colucci VJ, Berry BD. Ann Pharmacother 2008;42: Therapeutic Guidelines: Psychotropic. Version 5, Ellis PM, Smith DAR. MJA 2002;176 Suppl:S National Institute for Health and Clinical Excellence. Depression (amended): management of depression in primary and secondary care. NICE clinical guideline 23 (amended). 2004, /nicemedia/pdf/cg23niceguidelineamended.pdf (accessed 23 April 2008). 9. Royal Australian and New Zealand College of Psychiatrists. Aust N Z J Psychiatry 2004;38: Hansen RA, et al. Ann Intern Med 2005;143: National Institute for Health and Clinical Excellence. Depression: Management of depression in primary and secondary care. National Clinical Practice Guideline Number 23 [Full Guideline] (accessed 29 April 2008). 12. Papakostas GI, et al. Biol Psychiatry 2007;62: Perahia DG, et al. J Psychiatr Res 2008;42: Khan A, et al. Clin Drug Investig 2007;27: Wade A, et al. Curr Med Res Opin 2007;23: US Food and Drug Administration. Antidepressant Use in Children, Adolescents, and Adults. Revisions to product labelling. /antidepressants/antidepressants_label_change_2007.pdf (accessed 7 May 2008). 17. Greist J, et al. Clin Ther 2004;26: McIntyre RS, et al. Expert Opin Drug Metab Toxicol 2008;4: AstraZeneca Pty Ltd. Toprol-XL product information. 12 January Sigma Pharmaceuticals (Australia) Pty Ltd. Pexsig product information. 22 October Hersh EV, et al. Clin Ther 2007;29 Suppl: Australian Medicines Handbook, Isbister GK, et al. Med J Aust 2007;187: Keks NA, et al. Med J Aust 2007;186: Dunner DL, et al. Curr Ther Res 2005;66: Whitmyer VG, et al. J Clin Psychiatry 2007;68: Hartford J, et al. Int Clin Psychopharmacol 2007;22: Eli Lilly and Company [USA]. Cymbalta (duloxetine) Prescribing Information. /foi/label/2007/021427s015s017lbl.pdf (accessed 23 April 2008). 29. Eli Lilly and Company Limited [UK]. Cymbalta summary of product characteristics, 28 August /displaydoc.asp?documentid=15694 (accessed 23 April 2008). 30. Perahia DG, et al. J Affect Disord 2005;89: Date prepared: June 2008 The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.

19 Escitalopram (Lexapro, Esipram) for generalised anxiety disorder and social anxiety disorder (social phobia) (ES-sigh-TAL-o-pram) Summary Escitalopram is the first PBS-subsidised selective serotonin reuptake inhibitor (SSRI) for moderate to severe generalised anxiety disorder (GAD) and moderate to severe social anxiety disorder (SAD/social phobia). GAD is excessive and uncontrolled worry about a number of events on most days for at least 6 months. SAD is fear and avoidance of social or performance situations. The PBS listing of escitalopram does not cover mild anxiety states for which other forms of treatment are more appropriate. Offer non-pharmacological therapies to all people with GAD and SAD, as these therapies can be effective. Patients prescribed escitalopram on the PBS must have failed non-pharmacological therapies and have a GP Mental Health Care Plan, or have been assessed by a psychiatrist. Start at a low dose and increase gradually over 2 4 weeks, if required. Monitor patients carefully in the first few weeks of treatment for a transient worsening of symptoms. GAD and SAD are chronic disorders. Patients who respond to escitalopram should continue treatment for at least 6 months. Refer patients with refractory GAD or SAD to a specialist mental health service. 18 PBS listing Restricted benefit Escitalopram is listed on the Pharmaceutical Benefits Scheme (PBS) as a restricted benefit for the treatment of major depressive disorder. The PBS listing has been extended to the treatment of moderate to severe generalised anxiety disorder (GAD) and moderate to severe social anxiety disorder (SAD, or social phobia [see Box 1]), in people for whom: non-pharmacological therapies have failed; and for whom a General Practice Mental Health Care Plan has been prepared; or assessment by a psychiatrist has occurred. 1 PBS-subsidised continuing treatment is available for people prescribed escitalopram before 1 March 2008 who may not have a GP Mental Health Care Plan, or have not been seen by a psychiatrist. Reason for PBS listing The Pharmaceutical Benefits Advisory Committee (PBAC) accepted trial data on the effectiveness of escitalopram compared with placebo for reducing anxiety in moderate to severe GAD and moderate to severe SAD. There are currently no other PBSsubsidised treatments for GAD or SAD, so listing was recommended on the basis of acceptable costeffectiveness compared with placebo. 2 To avoid use in populations in which there is no proven benefit (for example, people with mild anxiety), the PBAC restricted the listing of escitalopram to patients whose anxiety symptoms do not respond to non-pharmacological therapy. Non-pharmacological therapy in this context includes both formal psychological therapy and informal psychological therapy (for example, supportive counselling) provided by a GP. Patients can access a range of psychological services under the Medicare Benefits Scheme.

20 Escitalopram (Lexapro, Esipram) 19 This listing requires that a GP prepare a Mental Health Care Plan to promote appropriate assessment and a structured approach to care, or that a psychiatrist assesses the patient. Place in therapy Escitalopram is a selective serotonin reuptake inhibitor (SSRI) and the active isomer of citalopram. SSRIs are a recommended initial pharmacological option for long-term treatment of anxiety disorders. 3,4 Other antidepressants are indicated for GAD and SAD but are not PBS subsidised for these indications. Paroxetine and venlafaxine are TGA approved for both disorders, and sertraline for SAD. 5 Evidence for the efficacy of escitalopram is limited to patients with a primary diagnosis of moderate to severe GAD or moderate to severe generalised SAD, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) (see Box 1). It does not relate to mildly anxious patients, for whom other forms of treatment are more appropriate. Box 1: Generalised anxiety disorder (GAD) and social anxiety disorder (SAD/social phobia) Generalised anxiety disorder (GAD) Excessive and inappropriate anxiety and worry about several events or activities, more days than not, lasting at least 6 months. Additional symptoms must include at least three of the following: restlessness easily fatigued difficulty concentrating irritability muscle tension sleep disturbance. 6 Social anxiety disorder (SAD/social phobia) Marked, persistent and unreasonable fear of scrutiny by others and avoidance of social or performance situations in which embarrassment may occur. Feared situations are usually avoided or endured with intense anxiety and distress. 6 In severe cases, SAD causes significant interference with occupational, academic and social functioning and interpersonal relationships. Two distinct subtypes of SAD exist: generalised SAD (fear and avoidance of most performance and social situations) and non-generalised SAD (fear of particular performance situations as well as several but not all social situations). 6 Escitalopram was shown in trials to be more effective than placebo in reducing anxiety in more severe forms of GAD and SAD. There is no evidence that it is more effective than other SSRIs in these indications. Psychological therapies, including cognitive behavioural therapy (CBT), are also an effective initial option for anxiety disorders. 3,4,7 9 Consider escitalopram in conjunction with a structured plan of care for people with moderate to severe GAD or SAD who fail to respond to non-pharmacological therapies alone. Aim to control symptoms and improve social functioning The main treatment options for anxiety disorders include psychological therapy, pharmacological therapy and self-help strategies. 3,4,7,8 Choose a treatment based on factors including: patient preference type, severity and persistence of anxiety presence of psychiatric or physical comorbidity response to previous treatments availability of psychological therapies. 4 Try non-pharmacological therapies first Psychological therapies are effective and should be offered as an initial treatment option to people with GAD and SAD. 7,8 Cognitive behavioural therapy is likely to be at least as effective as pharmacological therapy in the treatment of GAD and SAD, and possibly with longer-term benefits When available and acceptable to the patient, offer an adequate course of CBT (for example weekly sessions of 1 2 hours for up to 4 months). 3 Internet-based psychological interventions may be useful for some patients 3 (see Resources for patients and clinicians). While combining CBT with pharmacological therapy may help patients who are not responding to an adequate trial of either treatment alone, there is little trial evidence to inform this approach. 11 Efficacy of escitalopram in practice may be lower than expected from trial results The clinical relevance of small but statistically significant treatment differences between escitalopram and placebo, as seen in clinical trials, remains unclear. Patients with significant physical or psychiatric